Jeremy Naftali Rich
Adjunct Associate Professor in the Department of Neurology
Laboratory of Brain Tumor Signal Transduction
Malignant gliomas remain essentially incurable, despite maximal therapy. Traditional treatments for these cancers rely on non-specific, cytotoxic approaches that generally act through damaging DNA and have marginal impact on patient survival. However, advances in the understanding of the molecular biology underlying glioma pathogenesis have indicated abnormalities in a set of common cellular pathways and functions among the majority of these tumors, which are now being targeted by novel agents in preclinical and clinical development. These treatments may offer the promise of improved tumor control without substantial toxicity, but significant challenges remain in their development, including the inability to predict tumor response prior to treatment and limitations of drug delivery into the tumor. Our laboratory focuses on the elucidation of the basic regulation of tumor cell behavior and the translation of novel low molecular weight inhibitors of signal transduction pathways into brain tumor therapies. Specific areas of research include:
Targeting DNA Damage Checkpoint Signaling in Glioma Radioresistance
(Investigators: Shideng Bao, Quilian Wu, Sith Sathornsumetee) Ionizing radiation (IR) is the most effective therapeutic modality for gliomas, but radiotherapy remains palliative due to universal radioresistance. IR induces cell cycle arrest and/or apoptosis, largely through double strand DNA breaks. In the initial cellular response to radiation, these breaks activate the DNA damage/replication checkpoint, driving the cell either towards cell cycle arrest or apoptosis. We are investigating the roles that key regulatory proteins of the DNA damage checkpoint signaling cascade – ATM, Rad17 and Chk2 – play in glioma radiation resistance.
Responses to transforming growth factor-β shift towards tumor suppression in the presence of the Pten tumor suppressor gene
(Investigators: Anita B. Hjelmeland, Mark D. Hjelmeland, Audra Lee): Transforming growth factor-β (TGFβ) is a multifunctional cytokine commonly expressed by advanced cancers that regulates a diverse set of biological activities, including proliferation, apoptosis, differentiation, motility, extracellular matrix deposition, and angiogenesis. Although glial cells are growth inhibited by TGFβ, glioma cell lines are resistant to TGFβ-mediated growth inhibition yet remain responsive to the effects of TGFβ that promote tumorigenesis – secretion of angiogenic factors, induction of invasion, and immune escape. The molecular mechanisms through which TGFβ shifts from a tumor suppressor to a tumor enhancer during cancer progression are relatively unknown. We have shown that the loss of PTEN expression may promote cellular responses to TGFβ involved in tumor progression. Reintroduction of PTEN may shift TGFβ cellular responses towards a tumor suppressive phenotype by restoring sensitivity of glioma cell lines to TGFβ-mediated growth inhibition while blocking TGFβ-mediated invasion. We continue to explore the molecular mechanisms through which these effects are mediated and determine the impact on targeted therapies regulating these pathways.
The Roles of Secreted Protein Acidic and Rich in Cysteine (SPARC) in Brain Tumor Invasion
(Investigators: Qing Shi, Shideng Bao): Although the molecular events underlying tumor invasion remain poorly understood, invasion of normal brain contributes to the overwhelming lethality of malignant gliomas. We recently linked poor survival of glioblastoma patients to expression of secreted protein, acidic and rich in cysteine (SPARC, also known as osteonectin). SPARC is a glycoprotein overexpressed in gliomas, particularly at sites of tumor invasion into normal brain. We and others previously demonstrated that expression of SPARC in human glioma cell lines induces an invasive phenotype associated with increased expression of matrix metalloproteinases (MMPs). In addition, we have shown that SPARC stimulates Akt phosphorylation and survival under stress. Based on these data and additional Preliminary Results, we now hypothesize that SPARC expression contributes to glioma invasion through activation of specific intracellular pathways and that these processes can be disrupted to block glioma invasion.
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